The pathogenesis of misfolded protein disorders is characterized by the conversion of normal proteins into aggregation-prone β-sheet rich conformations. These conformations are implicated in amyloidogenic disease. In the case of Alzheimer's Disease (AD), self-assembly of amyloid beta (Aβ) protein into neurotoxic oligomers and fibrils is a leading postulation in regard to a major mechanism that causes AD.
Alzheimer's diseases is associated with a specific structural form of the Aβ protein (e.g., a “misfolded protein” or a self-aggregated protein), while the protein in a different structural form (e.g., a “normal protein”) is not harmful. Misfolded Aβ protein form aggregates that self-assemble into non-branching fibrils with the common characteristic of a β-pleated sheet conformation. In the central nervous system (CNS), amyloid deposits can be present in cerebral and meningeal blood vessels (cerebrovascular deposits) and in brain parenchyma (plaques). Neuropathological studies in human and animal models indicate that cells proximal to amyloid deposits are disturbed in their normal functions. See, e.g., Mandybur, Acta Neuropathol. 78:329-331, 1989; Kawai et al., Brain Res. 623:142-146, 1993; Martin et al., Am. J. Pathol. 145:1348-1381, 1994; Kalaria et al., Neuroreport 6:477-80, 1995; Masliah et al., J. Neurosci. 16:5795-5811, 1996. Other studies additionally indicate that amyloid fibrils may actually initiate neurodegeneration. See, e.g., Lendon et al., J. Am. Med. Assoc. 277:825-831, 1997; Yankner, Nat. Med. 2:850-852, 1996; Selkoe, J. Biol. Chem. 271:18295-18298, 1996; Hardy, Trends Neurosci. 20:154-159, 1997.
While the underlying molecular mechanism that results in protein misfolding is still not completely understood, a common characteristic is the propensity to form aggregates and/or fibrils which exhibit a β-sheet structure or other conformations. Fibril formation and the subsequent formation of secondary β-sheet structures associated with plaque deposits, occurs via a complex mechanism involving a nucleation stage, in which monomers of the protein associate to form oligomers, which associate to form fibrils, followed by extension of the fibrils at each end. For example, Aβ protein monomers can be found in various parts of healthy individuals, including body fluids (e.g., blood and cerebrospinal fluid) and tissue (e.g., brain). Disease caused by misfolded Aβ protein appears to correlate with self-assembly of the monomers into oligomers (soluble aggregates), insoluble oligomers (e.g., insoluble amorphous self-aggregates), protofibrils, or fibrils, eventually forming into non-soluble, large aggregated deposits such as plaques found in diseased individuals.
Two abundant forms of Aβ protein found in amyloid plaques are Aβ1-40 (also referred to as Aβ40) and Aβ1-42 (also referred to as Aβ42). Although Aβ1-40 is more abundant, Aβ42 is the more fibrillogenic and is the major component of the two in amyloid deposits of both AD and CAA. See, e.g., Wurth et al., J. Mol. Biol. 319: 1279-90 (2002). In addition to the amyloid deposits in AD cases described above, AD cases can be associated with amyloid deposition in the vascular walls. See, e.g., Vinters H. V., Stroke March-April; 18(2):311-324, 1987; Itoh Y., et al., Neurosci. Lett. 155(2):144-147, Jun. 11, 1993.
There is a need, therefore, for methods of detecting Aβ oligomers, which can provide insight into the risk for, presence, progression, severity and prognosis of disease and/or the efficacy of therapeutic agents aimed at disrupting the formation of Aβ protein aggregates.